The noradrenergic system is implicated in neuropathologies contributing to major disorders of the memory, including post-traumatic stress disorder and Alzheimer’s disease. Determining the impact of norepinephrine on cellular function and plasticity is thus essential for making inroads into our understanding of these brain conditions, while expanding our capacity for treating them. Norepinephrine is a neuromodulator within the mammalian central nervous system which plays important roles in cognition and associated synaptic plasticity. Specifically, norepinephrine regulates the formation of memory through the stimulation of β-ARs, increasing the dynamic range of synaptic modifiability. The mechanisms through which NE influences neural circuit function have been extended to the level of the epigenome. This review focuses on recent insights into how the noradrenergic recruitment of epigenetic modifications, including DNA methylation and post-translational modification of histones, contribute to homo- and heterosynaptic plasticity. These advances will be placed in the context of synaptic changes associated with memory formation and linked to brain disorders and neurotherapeutic applications.

Rationale: The hyperactivity of lateral habenula (LHb) has been implicated in the pathophysiology of depression, but the regulatory mechanisms of inhibitory synapses in this context remains unclear. MDGA1 and neuroligin2 (Nlgn2), both regulators of inhibitory synapses, selectively interact in the LHb. We aimed to investigate if their interaction contributes to chronic restrained stress (CRS)-induced depression by modulating inhibitory synapses.